Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia.
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Embargo End Date
ICR Authors
Authors
Turati, VA
Guerra-Assunção, JA
Potter, NE
Gupta, R
Ecker, S
Daneviciute, A
Tarabichi, M
Webster, AP
Ding, C
May, G
James, C
Brown, J
Conde, L
Russell, LJ
Ancliff, P
Inglott, S
Cazzaniga, G
Biondi, A
Hall, GW
Lynch, M
Hubank, M
Macaulay, I
Beck, S
Van Loo, P
Jacobsen, SE
Greaves, M
Herrero, J
Enver, T
Guerra-Assunção, JA
Potter, NE
Gupta, R
Ecker, S
Daneviciute, A
Tarabichi, M
Webster, AP
Ding, C
May, G
James, C
Brown, J
Conde, L
Russell, LJ
Ancliff, P
Inglott, S
Cazzaniga, G
Biondi, A
Hall, GW
Lynch, M
Hubank, M
Macaulay, I
Beck, S
Van Loo, P
Jacobsen, SE
Greaves, M
Herrero, J
Enver, T
Document Type
Journal Article
Date
2021-07-05
Date Accepted
2021-05-11
Abstract
Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy.
Citation
Nature Cancer, 2021, 2 (8), pp. 835 - 852
Source Title
Nature Cancer
Publisher
NATURE PORTFOLIO
ISSN
2662-1347
eISSN
2662-1347
2662-1347
2662-1347
Collections
Research Team
Evol Genomics & Modelling
Biol Childhood Leukaemia
Biol Childhood Leukaemia